Use of efaroxan for producing medicine for treating huntington &#39;s disease

ABSTRACT

The invention concerns the use of efaroxan or therapeutically-acceptable salts, in its racemic form or in the form of an optically-active isomer, for treating Huntington&#39;s disease.

The present application is a U.S. National Application filed under 35USC 371 of PCT/FR97/01480, filed Aug. 12, 1997 based upon Frenchapplication Serial No. 96/10118 filed Aug. 12, 1996.

The present invention relates to the use of Efaroxan, which is thecompound of the following formula: ##STR1## as well as itstherapeutically acceptable salts, its racemic form or its opticallyactive isomers, for the preparation of a medicinal product for thetreatment of Huntington's disease.

The subject of the present invention is the use of Efaroxan to obtain aneuroprotective medicinal product for the treatment of Huntington'sdisease and its progression.

Huntington's disease is considered as a pathological consequence oflesions of the GABA-ergic and cholinergic systems in the striatum whichare caused by excitotoxic substances on the complex: ion channels-NMDAreceptor.

The clinical manifestations of Huntington's disease are motor disorders,in particular abnormal choreiform movements which gradually worsen andare subsequently accompanied by bradykinesia and muscular rigidity, aswell as by neuropsychiatric problems such as depression, suicidaltendencies and personality and cognitive disorders. These disorders arevery soon manifested by a loss of visuospatial acuity which can precedethe choreiform movements by a few years, with cognitive loss as isobserved in patients whose frontal lobe is affected.

One particular aspect of the disease is memory loss, in particular therecall function. In neuropathological terms, one characteristic of thedisease is a marked atrophy of the corpus striatum, in which theefferent systems and interneurones are affected, along with pronouncedgliosis. To a lesser extent, the same phenomenon is observed in theglobus pallidus, the thalamus, the substantia nigra, the locus coeruleusand the cortex.

No treatment is currently available to care for or delay the developmentof Huntington's disease.

It is known that Efaroxan:2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline, has antagonisticproperties on the α₂ -adrenergic receptors. This compound is describedin patent application GB 2,102,422, as is its therapeutic application asan antidepressant and antimigraine medicinal product. This compound isalso described in patent application WO 92/05171, which reveals theaction of the levo-rotatory enantiomer to treat diabetes, as an agentfor blocking the potassium channels.

Our patents WO 94/00715 and WO 94/00841 also relate to the use ofEfaroxan in the treatment of Parkinson's disease and in Alzheimer'sdisease.

The present invention relates to the use of Efaroxan for the preparationof a medicinal product for the treatment of Huntington's disease.

The term Efaroxan refers to the compound of formula: ##STR2## itstherapeutically acceptable salts, its racemic mixture or its opticallyactive isomers.

Pharmacological Study

Quinolinic acid, an endogenous metabolic of tryptophan, acts as apowerful agonist on the NMDA receptor (Eur. J. Pharm (1981), 72, 411).When injected into the striatum in rats and monkeys, it causesneurochemical and morphological changes similar to those observed inHuntington's disease (Life Sci. (1984), 35, 19) and are reflected by adeficiency in spatial acuity, cognitive abilities and recall. Thisattack of the striatum thus accounts for Huntington's disease (Behav.Brain Res. (1987), 24, 125).

In brains affected by the disease, the level of enzyme for the synthesisof quinolinic acid, 3-hydroxy-anthranilate oxygenase (3-HAO), is high.Furthermore, the level of kynurenic acid (another tryptophan metaboliteand a quinolinic acid antagonist) is lowered, thus implying a poorbalance between these two acids--quinolinic acid and kynurenic acid--inbrains affected by Huntington's disease (Pharmacol. Rev. 1993, 45, 309).

Thus, a pharmacological intervention capable of restoring the functionsof the striatum in this model can be useful in the treatment of themotor and cognitive manifestations of Huntington's disease in man (J.Neuroscience (1988), 8, 3901 and Pharmacol. Rev. (1993), 45, 309).

The parameters measured are:

1) The activity of choline acetyltransferase (ChAT) in the striatum,which is a marker of the cholinergic neurones in this part of the brain.A reduction in the activity of ChAT, following an intrastriatalinjection of quinolinic acid, is a quantitative measure of the loss ofstriatal cholinergic neurones, and is correlated with the extent of theneurotoxic lesion in that part of the brain. In this model, the abilityof a drug to attenuate the loss of ChAT activity, induced by quinolinicacid, is considered as an indication of a protective or restorativeeffect of the integrity of the striatal cholinergic system. This modelused is described by T. W. Stone (Pharmacol. Rev. 1993, 45, 309), M. F.Beal et al. (J. Neurosci. 1988, 8, 3901) and M. Miyamoto and J. T. Coyle(Exptl. Neurol. 1990, 108, 38).

2) The rotational behavior induced by apomorphine, which is an indicatorof dysfunction of the efferent striatal system, this model beingdescribed by C. J. Pycock (Neuroscience, 1980, 5, 461). That publicationreviews the evidence demonstrating that unilateral lesions in thestriatum by exitotoxins, such as quinolinic acid, give rise to arotational (ipsilateral) behavior in animals which have receivedapomorphine, and that the intensity of these rotations is in relationwith the extent of the lesion. The ability of a drug to reduce thenumber of rotations induced by apomorphine is considered as indicativeof a protective or restorative effect of the integrity of efferentstriatal neurone function.

The results are as follows:

1) ChAT Activity

ChAT is decreased to 26±8% (mean±SEM) of the normal activity (measuredin undamaged striatum), 2 weeks after intrastriatal unilateral injectionof quinolinic acid (150 nmol) to rats.

Administration 3 times a day for 7 days of 0.63 mg/kg of Efaroxan fromthe same day of the injection of quinolinic acid, partially attenuatesthis loss of ChAT activity. In this case, the activity is reduced onlyto 56±7% (mean±SEM) of the normal activity, as can be seen in theattached FIG. 1, which illustrates the loss of ChAT activity induced byquinolinic acid in rat striatum, and thus reflects the protective effectexerted.

2) Rotation Behavioral Test

In the animals injured with quinolinic acid as above, an injection of0.63 mg/kg of apomorphine two weeks later induces an ipsilateralrotation (256±29 rotations/h, mean±SEM). The administration of 0.63mg/kg of Efaroxan as above, 3 times a day for 7 days, reduces the numberof these ipsilateral rotations by 43% (to 147±24 rotations/h, mean±SEM),as shown in the attached FIG. 2 which illustrates the rotations inducedby apomorphine in rats injured with quinolic acid and demonstrates theattenuation of the effect by Efaroxan.

The above results show the advantage of Efaroxan for reducing thedeleterious excitotoxic effects of quinolinic acid in the striatum, andits advantage in the prevention of neurotoxic disorders in which theglutamate receptors are involved.

Efaroxan thus has an advantage for use as a medicinal product to treator delay or prevent the development of Huntington's disease.

Pharmaceutical Study

The pharmaceutical compositions forming part of the invention areadministered orally to man, in one or more doses, in the form of gelatincapsules or tablets containing a dose of from 1 to 200 mg of activeprinciple, more particularly of 7, 20, 30 and 40 mg per tablet, orintravenously in the form of an injectable solution containing a dose offrom 0.1 to 10 mg of Efaroxan.

Clinical Study

Efaroxan was administered at a dose of 30 mg 3 times a day to a group ofpatients exhibiting the symptomatology of Huntington's disease. Theresults show an improvement in behavior in about 30% of the cases.

What is claimed is:
 1. Method of treating Huntington's Diseasecomprising the step of administering to a patient suffering therefrom aneffective amount of Efaroxan or a therapeutically-acceptable saltthereof in racemic form or in the form of an optically-active isomerthereof.
 2. Method of claim 1 wherein the Efaroxan or atherapeutically-acceptable salt thereof is administered orally in theform of a pharmaceutical composition containing 7 to 40 mg of Efaroxanor therapeutically-acceptable salt thereof per unit dosage form.
 3. Themethod of claim 2 wherein the pharmaceutical composition is administeredin the form of gelatin capsules or tablets.
 4. The method of claim 2wherein the pharmaceutical composition is administered in unit dosageform a plurality of times a day.
 5. The method of claim 4 wherein thepharmaceutical composition is administered in 30 mg dosages three timesa day.
 6. The method of claim 1 wherein the Efaroxan ortherapeutically-acceptable salt thereof is administered in the form ofan injectable solution containing 0.1 to 10 mg of Efaroxan ortherapeutically-acceptable salt thereof per unit dose.